Mitogen-activated Protein Kinase ERK1/2 Regulates the Class II Transactivator

The expression of major histocompatibility class II genes is necessary for proper antigen presentation and induction of an immune response. This expression is initiated by the class II transactivator, CIITA. The establishment of the active form of CIITA is controlled by a series of post-translationa...

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Bibliographic Details
Published in:	The Journal of biological chemistry Vol. 283; no. 14; pp. 9031 - 9039
Main Authors:	Voong, Lilien N., Slater, Allison R., Kratovac, Sebila, Cressman, Drew E.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 04-04-2008 American Society for Biochemistry and Molecular Biology
Subjects:	Active Transport, Cell Nucleus - physiology Amino Acid Substitution Animals Antigen Presentation - physiology Cell Nucleus - genetics Cell Nucleus - immunology Cell Nucleus - metabolism Chlorocebus aethiops COS Cells Dimerization Exportin 1 Protein Guanosine Triphosphate - genetics Guanosine Triphosphate - immunology Guanosine Triphosphate - metabolism Histocompatibility Antigens Class II - blood Histocompatibility Antigens Class II - genetics Histocompatibility Antigens Class II - metabolism Humans Karyopherins - genetics Karyopherins - immunology Karyopherins - metabolism Mice Mitogen-Activated Protein Kinase 1 - genetics Mitogen-Activated Protein Kinase 1 - immunology Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - genetics Mitogen-Activated Protein Kinase 3 - immunology Mitogen-Activated Protein Kinase 3 - metabolism Mutation, Missense Nuclear Proteins - genetics Nuclear Proteins - immunology Nuclear Proteins - metabolism Phosphorylation Promoter Regions, Genetic - physiology Protein Binding - physiology Protein Processing, Post-Translational - physiology Protein Synthesis, Post-Translational Modification, and Degradation Receptors, Cytoplasmic and Nuclear - genetics Receptors, Cytoplasmic and Nuclear - immunology Receptors, Cytoplasmic and Nuclear - metabolism Trans-Activators - genetics Trans-Activators - immunology Trans-Activators - metabolism Ubiquitination - physiology
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Summary:	The expression of major histocompatibility class II genes is necessary for proper antigen presentation and induction of an immune response. This expression is initiated by the class II transactivator, CIITA. The establishment of the active form of CIITA is controlled by a series of post-translational events, including GTP binding, ubiquitination, and dimerization. However, the role of phosphorylation is less clearly defined as are the consequences of phosphorylation on CIITA activity and the identity of the kinases involved. In this study we show that the extracellular signal-regulated kinases 1 and 2 (ERK1/2) interact directly with CIITA, targeting serine residues in the amino terminus of the protein, including serine 288. Inhibition of this phosphorylation by dominant-negative forms of ERK or by treatment of cells with the ERK inhibitor PD98059 resulted in the increase in CIITA-mediated gene expression from a class II promoter, enhanced the nuclear concentration of CIITA, and impaired its ability to bind to the nuclear export factor, CRM1. In contrast, inhibition of ERK1/2 activity had little effect on serine-to-alanine mutant forms of CIITA. These data suggest a model whereby ERK1/2-mediated phosphorylation of CIITA down-regulates CIITA activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 To whom correspondence should be addressed: 1 Mead Way, Bronxville, NY 10708-5999. Tel.: 914-395-2434; Fax: 914-395-2662; E-mail: dcressma@slc.edu. This work was supported by National Science Foundation Grant MCB0515853 and a grant from the Sara Lee Schupf Foundation (to D. E. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.M706487200